This invention relates to substituted compounds of formula (I): 
wherein Ar1, Ra, R4, R5, X and Y are defined below, which are useful as inhibitors of certain protein tyrosine kinases and are thus useful for treating diseases resulting from inappropriate cell proliferation, which include autoimmune diseases, chronic inflammatory diseases, allergic diseases, transplant rejection and cancer, as well as conditions resulting from cerebral ischemia, such as stroke. This invention also relates to processes for preparing these compounds and to pharmaceutical compositions comprising these compounds.
Tyrosine kinases play an essential role in the regulation of cell signaling and cell proliferation by phosphorylating tyrosine residues of peptides and proteins. Inappropriate activation of tyrosine kinases is known to be involved in a variety of disease states, including immunologic and oncologic disorders.
It has been well established that T cells play an important role in regulating the immune response (F. Powrie and R. L. Coffman, Immunol. Today, 1993, 14, 270). Activation of T cells is often the initiating event in many inflammatory and autoimmune diseases. In addition to their role in immune surveillance, T cells can become autoreactive by recognizing self-antigens and thereby cause autoimmune disease such as rheumatoid arthritis and inflammatory bowel disease.
The T cell receptor (TCR) is the antigen-specific component of the T cell and is activated when the receptor is engaged with foreign or self-antigenic peptides. When the TCR is activated a series of enzyme-mediated signal transduction cascades is initiated which results in the production of pro-inflammatory cytokines such as interleukin-2 (IL-2).
The release of IL-2 is critically important since this lymphokine is required for T-lymphocyte proliferation, differentiation, and effector function. Clinical studies have shown that interference with IL-2 activity effectively suppresses immune response in vivo (T. A. Waldmann, Immunol. Today, 1993, 14, 270). Accordingly, agents which inhibit T-lymphocyte activation and subsequent IL-2 production, or block the activity of IL-2 are therapeutically useful for selectively suppressing immune response in a patient in need of such immunosuppression.
The eight members of the src family of tyrosine kinases are src, lck, fyn, lyn, hck, fgr, blk and yes (J. B. Bolen, J. S. Brugge, Ann. Rev. Immunol., 1997, 15, 371). These can be divided into 2 groups based on their pattern of tissue expression. Src, fyn and yes have a broad distribution while expression of lck, lyn, hck, fgr, and blk is largely limited to hemopoietic cells. The therapeutic effects of inhibiting kinases of the src family can be ascertained by linking functional defects seen in gene disruption studies in mice. Src(xe2x88x92/xe2x88x92) mice had severe abnormalities in bone remodeling. Inhibition of src may therefore be useful in treating osteoporosis. Lck(xe2x88x92/xe2x88x92) mice display a complete lack of CD4+ cells and are unable to mount antigen-dependent immune responses.
A kinase of particular interest is p56lck, which is only expressed in T-cells. Within the TCR signal transduction cascade the tyrosine kinase p56lck is a required element to initiate the activation response from the TCR intracellular domains to other signaling proteins. For example, T cells which lack the p56lck protein are unable to signal through the T cell receptor (D. B. Straus and A. Weiss, Cell, 1992, 70, 585). Transfection of p56lck back into these cell lines restores TCR responsiveness. Also, it has been shown in mice that inactivation of the p56lck gene leads to lack of proper thymocyte development (T. J. Molina et al., Nature, 1992, 357, 161).
The conclusion drawn from these studies is that p56lck plays a crucial role in T cell maturation and antigen-induced T-cell activation. Therefore, an agent blocking pS56lck would effectively block T cell function, act as an immunosuppressive agent and have potential utility in autoimmune diseases, for example rheumatoid arthritis, multiple sclerosis, lupus, transplant rejection and allergic diseases (J. H. Hanke et al., Inflamm. Res., 1995, 44, 357).
Inhibitors of other members of the src family of non-receptor tyrosine kinases are also useful for treating various disease states. Src is present in osteoclasts, and is important in bone remodeling. For example, inactivation of p60src diminishes bone resorption by osteoclasts (P. Soriano et al., Cell 1991, 64, 693, B. F. Boyce et al. J Clin. Invest 1992, 90, 1622), it is therefore possible that inhibitors of the kinase activity of p60src are useful in the treatment of osteoporosis, Paget""s disease and inflammation of bones and joints.
Src kinases have been found to be activated in tumors, including breast and colon cancers, melanoma and sarcoma. For example, a number of primary tumors and tumor cell lines from patients with breast cancer, colon cancer, melanoma and sarcoma have been shown to have elevated src kinase activity, and activating src mutations are seen in some advanced colon cancers. Inhibitors of src kinase had significant antiproliferative activity against cancer cell lines (M. M. Moasser et al., Cancer Res., 1999, 59, 6145) and inhibited the transformation of cells to an oncogenic phenotype (R. Kami et al., Oncogene, 1999, 18, 4654) suggesting that src kinase inhibitors may be useful anti-cancer agents.
Src inhibitors have also been reported to be effective in an animal model of cerebral ischemia (R. Paul et al. Nature Medicine 2001, 7, 222), suggesting that src kinase inhibitors may thus be useful in treating conditions involving cerebral ischemia. For example, src kinase inhibitors may be useful in reducing brain damage following stroke.
In addition, src family kinases participate in signal transduction in several cell types. For example, fyn, like lck, is involved in T-cell activation. Hck and fgr are involved in Fc gamma receptor mediated oxidative burst of neutrophils. Src and lyn are believed to be important in Fc epsilon induced degranulation of mast cells, and so may play a role in asthma and other allergic diseases. The kinase lyn is known to be involved in the cellular response to DNA damage induced by UV light (T. Hiwasa, FEBS Lett. 1999, 444, 173) or ionizing radiation (S. Kumar, J Biol Chem, 1998, 273, 25654). Inhibitors of lyn kinase may thus be useful as potentiators in radiation therapy.
Platelet derived growth factor is a potent mitogen for smooth muscle cells. Its receptor (PDGFR) is a member of the receptor tyrosine kinase family (L. Claesson-Welsh, J Biol Chem, 1994, 269, 32023). PDGF is involved in atherosclerosis and restenosis (K. E. Bomfeldt, Trends Cardiovasc. Med., 1996, 6, 143). In addition, receptor tyrosine kinases including PDGFR kinase have been implicated as contributing factors in cancer (A. Levitzki and A. Gazit, Science, 1995, 267, 1782) including ovarian (M. B. Dabrow et al., Gynecologic Oncology, 1998, 71, 29) and prostate (S.M. Sintich et al., Endocrinology, 1999, 140, 3411) cancers and glioblastoma (B. J. Silver, BioFactors, 1992 3, 217). Inhibitors of PDGFR kinase are thus useful in the treatment of fibrotic diseases, restenosis and PDGF-dependent tumors.
Reports have appeared in the literature of agents that inhibit the kinase activity of pS6lck kinase and thus inhibit T cell activation. These include the natural product lavendustin A, and analogs (M. S. Smyth, J. Med. Chem., 1993, 36, 3010), the natural product damnacanthal (C. R. Faltynek et al., Biochemistry, 1995, 34, 12404), and a 1-methoxy agroclavine isolated from a fungal extract (R. Padmanabha et al. Bioorganic and Med. Chem. Letters, 1998, 8, 569). Other inhibitors reported include WIN 61651 (J. Enzyme Inhibition, 1995, 9, 111) pyrazolopyrimidines PP1 and PP2 (Hanke et al. J Biol Chem, 1996, 271, 695) and indanone and indandione derivatives (J. L. Bullington et al., Bioorganic and Med. Chem. Letters, 1998, 8, 2489).
A. P. Spader et al. (WO 98/54157, 1998) describe quinoline and quinoxaline compounds that inhibit p56lck and PDGFR kinase. Fused polycyclic 2-aminopyrimidine derivatives that inhibit p56lck are reported by J. M. Davis et al. (WO 98/28281, 1998). J. Das et al. claim a series of benzothiazole amides as inhibitors of lck and other src family kinases (WO 99/24035, 1999). Inhibitors of PDGFR kinase and src-family kinases were reviewed by H. D. H. Showalter, A. J. Kraker, Pharmacol. Ther., 1997, 76, 55. Several patents on inhibitors of lck are reviewed in P. M. Traxler, Exp. Opin. Ther. Patents, 1997, 7, 571,and P.M. Traxler, Exp. Opin. Ther. Patents, 1998, 8, 1599.
U.S. Pat. No. 4,176,184 discloses imidazoisoquinoline-diones, which are described as being useful as cardiotonics, hypotensives, antithrombotics and antiarrhythmics. DE 3410168 Al discloses imidazoisoquinoline-dione derivatives, these compounds are described as being useful as cardiotonic agents in which the substituent on the fused imidazole ring is a pyridine ring bridged to the imidazole carbon by a C1-C4 alkyl group, a vinyl group or a chemical bond. EP 322 746 Al discloses heterocyclic lactam derivatives described as being useful as cardiotonic agents, antihypertensive agents and vasodilators.
The compounds of the present invention represent a novel structural class, which is distinct from previously reported tyrosine kinase inhibitors.
The work cited above supports the principle that inhibition of the kinases mentioned above will be beneficial in the treatment of various disease states.
It is therefore an object of the invention to provide novel compounds which inhibit PDGFR kinase and the src-family kinases including lck, src, fyn, lyn, hck, fgr, blk and yes.
It is a further object of the invention to provide methods for treating diseases and pathological conditions mediated by src-family tyrosine kinases and PDGFR kinase such as autoimmune diseases, transplant rejection, psoriasis, osteoporosis, Paget""s disease, cancer, including src-dependent tumors and PDGF-dependent tumors, cerebral ischemic conditions, atherosclerosis, restenosis and allergic diseases, using the novel compounds of the invention.
It is yet a further object of the invention to provide processes of preparation of the above-mentioned novel compounds and pharmaceutical compositions comprising the same.
The src-family tyrosine kinases and PDGFR kinase discussed above exhibit some homology in their amino acid structure. It is contemplated that due to structural differences between individual src-family kinases and PDGFR kinase, different compounds of the invention may have different inhibitory potencies against individual tyrosine kinases. Thus some of compounds of the invention may also be expected to be most effective in treating diseases mediated by tyrosine kinases that they inhibit most potently. Particular compounds disclosed herein have been shown to be active inhibitors of p56lck kinase, p60 src kinase and PDGFR kinase. See the section entitled xe2x80x9cAssessment of Biological Propertiesxe2x80x9d disclosed herein.
In its broadest generic aspect, the invention provides novel compounds of the formula I: 
wherein:
Ar1 is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle; wherein said carbocycle, heteroaryl or heterocycle is optionally substituted by one or more R1, R2 and R3;
X is NH, Nxe2x80x94C1-3alkyl, N-cyclopropyl, S or O;
Y is NR15, S or O;
Ra is H, C1-10alkyl, C2-10alkenyl or C2-10alkynyl, each of which may be branched or cyclic; or Ra is aryl or heteroaryl; wherein each Ra is independently optionally substituted with one or more C1-6alkyl, C1-6alkoxy, halogen, OH, oxo, NR10R11, aryl or heteroaryl, each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, C1-3alkyl, C1-3alkoxy, hydroxyC1-3alkyl and (CH2)mNR10R11, and wherein Ra is attached at the 4- or 5-position;
R1 and R2 are the same or different and selected from H, halogen, CN, NO2, C1-10 branched or unbranched saturated or unsaturated alkyl, C1-10 branched or unbranched alkoxy, C1-10 branched or unbranched acyl, C1-10 branched or unbranched acyloxy, C1-10 branched or unbranched alkylthio, aminosulfonyl, di-(C1-3)alkylaminosulfonyl, NR10R11, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the abovementioned R1 and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NR10R11, C1-6 branched or unbranched alkyl, C3-7cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(C1-3)alkylaminocarbonyl;
R3 is H, halogen, OH, (CH2)nNR10R11, CONR10R11, (CH2)nCO2R12; C1-3alkyl optionally substituted with OH, C1-3 alkoxy optionally halogenated or C1-3 alkylthio;
R4 and R5 together with the atoms to which they are attached complete a fused ring system of the formulas A or B: 
R6 is C1-3alkyl or H;
R7 is C1-6alkyl branched or unbranched or H;
R8 is H, C1-6alkyl branched or unbranched, saturated or unsaturated, optionally substituted with phenyl, OH or C1-3alkoxy; or R8 is (CH2)mNR10R11, (CH2)mNR10COR12, (CH2)nCO2R12, (CH2)nCONR10R11; or R8 is phenyl or heteroaryl, each being optionally substituted with C1-3alkyl, C1-3alkoxy, OH, xe2x80x94SO3H or halogen;
R9 is H, CN or CONR10R11; or R9 is C1-10alkyl branched or unbranched, C3-10cycloalkyl, C5-7cycloalkenyl, C2-6 alkenyl, C2-6 alkynyl each being optionally substituted with one or more C3-10cycloalkyl, C3-10cycloalkylidene, C5-7cycloalkenyl, halogen, OH, oxo, CN, C1-3alkoxy, C1-3acyloxy, NR10R11, NR10CONR10R11, NR10C(xe2x95x90NR10)NR10R11, NR10COR12, NR10S(O)pR12, SR12, CONR-10R11, CO2R12, C(R10)xe2x95x90NNR10R11, C(R10)xe2x95x90NNR10CONR10R11, aryloxy, arylthio, aryl or heteroaryl; wherein each aryloxy, arylthio, aryl or heteroaryl is optionally substituted with C1-3alkyl, C1-3alkoxy, halogen, (CH2)nNR10R11 or O(CH2)2-4NR10R11;
or R9 is aryl, heteroaryl, or heterocycle, wherein each aryl, heteroaryl or heterocycle is optionally substituted with one to three groups selected from C1-3alkyl optionally substituted with phenyl or NR10C(xe2x95x90NR10)NR10R11, C1-3alkoxy, halogen, CN, oxo, (CH2)nNR10R11, (CH2)nCO2R12; (CH2)nCONR10R11 and O(CH2)2-4NR10R11;
or R8 and R9 together form a saturated or unsaturated 5 or 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by one or two C1-3alkyl, OH, oxo or (CH2)nNR10R11, or optionally spiro-fused to a 1,3 dioxolane group or 1,3 dithiolane group, each 1,3 dioxolane group or 1,3 dithiolane group optionally substituted by C1-6alkyl, C1-6alkoxy, OH or (CH2)nNR10R11;
R10 and R11 may be the same or different and are each independently selected from H, OH, C1-3alkoxy, C1-6alkyl branched or unbranched, C3-8cycloalkyl, aryl, arylC1-3alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylC1-3alkyl or heteroaryl are optionally substituted with OH, C1-3alkoxy, CN, NO2, C1-3acyloxy, CO2R12, NR13R14, O(CH2)2-4NR13R14, aryl or heteroaryl;
or R10 and R11 together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached; wherein said alkylene chain is optionally interrupted by O, S(O)p, and NR13; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, OH, xe2x80x94(CH2)nNR13R14, CONR13R14 or NR13COR14;
R12 is H, C1-6alkyl or C3-8cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C1-3alkoxy or NR13R14; or R12 is phenyl or heterocycle, optionally substituted with one to three groups selected from C1-3alkyl, C1-3alkoxy, halogen, (CH2)mNR10R11, (CH2)nCONR10R11 and O(CH2)2-4NR10R11;
R13 and R14 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3alkoxy, OH or phenyl;
or R13 and R14 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2;
R15 is H or C1-3 alkyl;
m is 1-4; n is 0-3 and p is 0-2; and the pharmaceutically acceptable acid or salt derivatives thereof.
In one embodiment of the invention, there are provided compounds of the formula (I) described above, wherein:
Ar1 is
a) a cycloalkyl group selected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl;
b) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl, cycloheptenyl;
c) phenyl, naphthyl; indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl;
d) heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl, and indazolyl,or a fused heteroaryl selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; or
e) a heterocycle selected from pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl;
wherein each of the above Ar1 are optionally substituted by one or more R1, R2 and R3;
Ra is H, C1-6alkyl, C2-5alkenyl, C2-5alkynyl, phenyl or heteroaryl selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, furyl, thiazolyl and thienyl; each Ra being optionally substituted with one or more phenyl, halogen, C1-3alkyl, C1-3 alkoxy, OH, oxo, or NR10R11; wherein Ra is at the 4-position;
R1 and R2 are as hereinabove defined;
R3 is H, halogen, methyl, methoxy, hydroxymethyl or OH;
R8 is H, C1-3alkyl branched or unbranched, saturated or unsaturated, optionally substituted with OH; or R8 is (CH2)2-3NR10R11, (CH2)nCO2R12 or (CH2)nCONR10R11;
R9 is CN or CONR10R11; or R9 is C1-3alkyl branched or unbranched, C2-4 alkenyl, C2-4alkynyl each being optionally substituted with one or more C5-7cycloalkyl, C5-7 cycloalkylidene, C5-7cycloalkenyl,OH, CN, C1-3acyloxy, NR10R11, NR10CONR10R11, NR10C(xe2x95x90NR10)NR10R11, NR10COR12, NR10S(O)pR12, CONR10R11, CO2R12, C(R10)xe2x95x90NNR10R11, C(R10)xe2x95x90NNR10CONR10R11, aryl or heteroaryl; wherein each aryl or heteroaryl is optionally substituted with C1-3alkyl, C1-3alkoxy, halogen, (CH2)nNR10R11 or O(CH2)2-4NR10R11;
or R9 is aryl,heteroaryl or heterocycle, each optionally substituted with one to three groups selected from C1-3alkyl optionally substituted with phenyl or NR10C(xe2x95x90NR10)NR10R11, C1-3alkoxy, halogen, CN, oxo, (CH2)nNR10R11, (CH2)nCO2R12; (CH2)nCONR10R11 and O(CH2)2-4NR10R11;
or R8 and R9 together form a saturated or unsaturated 5 or 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by C1-3alkyl or OH, or optionally spiro-fused to a 1,3 dioxolane group or 1,3 dithiolane group, each 1,3 dioxolane group or 1,3 dithiolane group optionally substituted by C1-3alkyl, C1-3alkoxy, OH or (CH2)nNR10R11;
R10 and R11 may be the same or different and are each independently selected from H, OH, C1-3alkoxy, C1-6alkyl branched or unbranched, C3-8cycloalkyl, benzyl and phenyl;
wherein said alkyl, cycloalkyl, benzyl or phenyl are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CN, NO2, CO2R12, NR13R14, O(CH2)2-4NR13R14 or phenyl;
or R10 and R11 together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C1-3 alkyl, C1-3alkoxy, OH, xe2x80x94(CH2)nNR13R14, CONR13R14 or NR13COR14;
R12 is H, C1-6alkyl or C5-7cycloalkyl, each optionally substituted with phenyl, OH, C1-3alkoxy or NR13R14; or R12 is phenyl or heterocycle, each optionally substituted with one to three groups selected from C1-3alkyl, C1-3alkoxy, halogen, (CH2)mNR10R11, (CH2)nCONR10R11 and O(CH2)2-4NR10R11;
R13 and R14 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3alkoxy, OH or phenyl;
or R13 and R14 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2; and
R15 is H.
In another embodiment, there are provided compounds of the formula (I) described immediately above, wherein:
Ar1 is phenyl, or pyridyl, wherein each is optionally substituted by one or more
R1, R2 and R3 as defined below;
X is NH or Nxe2x80x94CH3;
Y is NH and
Ra is H, hydroxyC1-2alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo-propyl, vinyl or C3-5alkynyl substituted by C1-3alkoxy or phenyl;
R1 and R2 are the same or different and selected from: H, halogen, C1-3 alkyl, wherein the C1-3 alkyl are optionally partially or fully halogenated, NO2, NR13R14;
R3 is H, halogen, methoxy or methyl;
R4 and R5 together complete a fused ring of formula B;
R8 is H, C1-3alkyl optionally substituted with OH; or R8 is (CH2)2-3NR10R11 or CO2R12;
R9 is CN; or R9 is methyl, C2-3 alkenyl or C2-3 alkynyl, each being optionally substituted with one or more C5-7 cycloalkylidene, C5-7cycloalkenyl, OH, CN, NR10R11, NR10CONR10R11, NR10COR12, NR10S(O)pR12, CONR10R11, CO2R12, C(R10)xe2x95x90NNR10R11 or heteroaryl;
or R9 is aryl or heteroaryl optionally substituted with one to three groups selected from C1-3alkyl optionally substituted with phenyl, C1-3alkoxy, halogen, amino or CONH2;
or R8 and R9 together form a cyclopentene ring spiro-fused to a 1,3 dioxolane group, said 1,3 dioxolane group being optionally substituted by C1-3alkyl, C1-3alkoxy, OH or (CH2)nNR10R11;
R10 and R11 may be the same or different and are each independently selected from H, OH, C1-3alkoxy, C1-3alkyl branched or unbranched, C5-7cycloalkyl or phenyl, wherein said alkyl, cycloalkyl or phenyl are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, NO2, CO2R12, NR13R14, O(CH2)2-4NR13R14 or phenyl;
or R10 and R11 together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C1-3 alkyl, C1-3alkoxy,OH, (CH2)nNR13R14,CONR13R14 or NR13COR14;
R12 is H, C1-3alkyl or C5-7cycloalkyl, each optionally substituted with phenyl, OH, C1-3alkoxy or NR13R14; or R12 is phenyl or is a saturated, 4- to 6-membered nitrogen-containing heterocycle, each optionally substituted with one to three groups selected from C1-3alkyl, C1-3alkoxy, halogen, (CH2)mNR10R11, (CH2)nCONR10R11 and O(CH2)2-4NR10R11;
R13 and R14 are each independently selected from H and C1-3alkyl optionally substituted with C1-3alkoxy or OH;
or R13 and R14 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2.
In yet another embodiment, there are provided compounds of the formula (I) described immediately above, wherein:
Ar1 is phenyl;
Ra is H or hydroxymethyl;
R1 and R2 are the same or different and selected from: halogen, methyl optionally partially or filly halogenated, NO2 and NH2;
R3 is H, chloro, fluoro, bromo or methoxy;
R10 and R11 may be the same or different and are each independently selected from H, OH, methoxy, C1-3alkyl branched or unbranched or C5-7cycloalkyl, wherein said alkyl or cycloalkyl are optionally substituted with OH, NR13R14 or phenyl;
or R10 and R11 together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C1-2 alkyl, NR13R14, CONR13R14 or NR13COR14; and
R12 is C1-3alkyl optionally substituted with morpholino; or R12 is phenyl or is azetidinyl, pyrrolidinyl or piperidinyl, each optionally substituted with one to three groups selected from C1-3alkyl, C1-3alkoxy and halogen.
In another subgeneric aspect, the invention provides novel compounds of the formula I: 
wherein:
Ar1 is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle; wherein said carbocycle, heteroaryl or heterocyle is optionally substituted by one or more R1, R2 and R3;
X is NH, Nxe2x80x94C1-3alkyl, N-cyclopropyl, S or O;
Y is NR15, S or O;
Ra is H, C1-10alkyl, C2-10alkenyl or C2-10 alkynyl, each of which may be branched or cyclic;
or Ra is aryl or heteroaryl; wherein each Ra is independently optionally substituted with one or more C1-3alkyl, C1-6 alkoxy, halogen, OH, oxo, NR10R11, aryl or heteroaryl each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, C1-3alkyl, C1-3alkoxy, hydroxyC1-3alkyl and (CH2)mNR10R11, and wherein Ra is attached at the 4- or 5-position;
R1 and R2 are the same or different and selected from H, halogen, CN, NO2, C1-10 branched or unbranched saturated or unsaturated alkyl, C1-10 branched or unbranched alkoxy, C1-10 branched or unbranched acyl, C1-10 branched or unbranched acyloxy, C1-10 branched or unbranched alkylthio, aminosulfonyl, di-(C1-3)alkylaminosulfonyl, NR10R11, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the above mentioned R1 and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NR10R11, C1-6 branched or unbranched alkyl, C3-7Cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(C1-3)alkylaminocarbonyl;
R3 is H, halogen, OH, (CH2)nNR10R11, (CH2)nCO2R12; C1-3alkyl optionally substituted with OH, C1-3 alkoxy optionally halogenated or C1-3 alkylthio;
R4 and R5 together with the atoms to which they are attached complete a fused ring system of the formulas A or B: 
R6 is C1-3alkyl or H;
R7 is C1-6alkyl branched or unbranched or H;
R8 is H, C1-6 alkyl branched or unbranched, saturated or unsaturated, optionally substituted with phenyl, OH or C1-3alkoxy; or R8 is (CH2)mNR10R11, (CH2)mNR10COR12, (CH2)nCO2R12, (CH2)nCONR10R11; or R8 is phenyl or heteroaryl, each being optionally substituted with C1-3alkyl, C1-3alkoxy, OH, xe2x80x94SO3H or halogen;
R9 is H; or R9 is C1-10 alkyl branched or unbranched , C3-10 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl each being optionally substituted with one or more halogen, OH, oxo, CN, C1-3alkoxy, NR10R11, NR10COR12, SR12, CONR10R11, CO2R12, aryloxy, arylthio, aryl or heteroaryl; wherein each aryloxy, arylthio, aryl or heteroaryl is optionally substituted with C1-3alkyl, C1-3alkoxy, halogen, (CH2)nNR10R11 or O(CH2)2-4NR10R11;
or R9 is aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one to three groups selected from C1-3alkyl optionally substituted with phenyl, C1-3alkoxy, halogen, (CH2)nNR10R11, (CH2)nCO2R12; (CH2)nCONR10R11 and O(CH2)2-4NR10R11;
or R8 and R9 together form a saturated or unsaturated 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by one or two OH, oxo or (CH2)nNR10R11;
R10 and R11 may be the same or different and are each independently selected from H, OH, C1-3alkoxy, C1-6alkyl branched or unbranched, C3-8cycloalkyl, aryl, arylC1-3alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylC1-3alkyl or heteroaryl are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R1-2, NR13R14, O(CH2)2-4NR13 R14, aryl or heteroaryl;
or R10 and R11 together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached; wherein said alkylene chain is optionally interrupted by O, S(O)p, and NR13; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, OH or xe2x80x94(CH2),NR13R14;
R12 is H, C1-6alkyl or C3-8cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C1-3alkoxy or NR13R14; or R12 is phenyl, optionally substituted with one to three groups selected from C1-3alkyl, C1-3alkoxy, halogen, (CH2)mNR10R11, (CH2)nCONR10R11 and O(CH2)2-4NR10R11;
R13 and R14 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3alkoxy, OH or phenyl;
or R13 and R14 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2;
R15 is H or C1-3 alkyl;
m is 1-4, n is 0-3 and p is 0-2; and the pharmaceutically acceptable acid or salt derivatives thereof.
In one embodiment of the invention, there are provided compounds of the formula (I) as described immediately above, and wherein:
Ar1 is
a) a cycloalkyl group selected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl;
b) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl, cycloheptenyl;
c) phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl;
d) heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl, and indazolyl,or a fused heteroaryl selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; or
e) a heterocycle selected from: pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl;
wherein each of the above Ar1 are optionally substituted by one or more R1, R2 and R3 as hereinabove defined;
Ra is H, C1-6 alkyl, C2-5 alkenyl, C2-5 alkynyl, phenyl or heteroaryl selected from: pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, furyl, thiazolyl and thienyl; each Ra being optionally substituted with one or more phenyl, halogen, C1-3alkyl, C1-3 alkoxy, OH, oxo, or NR10R11; wherein Ra is at the 4-position;
R3 is H, halogen, methyl, methoxy, hydroxymethyl or OH;
R8 is H, C1-3alkyl branched or unbranched, saturated or unsaturated, optionally substituted with OH; or R8 is (CH2)2-3NR10R11 (CH2)nCO2R12 or (CH2)nCONR10R11;
R9 is C1-3alkyl branched or unbranched, C2-4 alkenyl, C2-4alkynyl each being optionally substituted with one or more OH, CN, NR10R11, CONR10R11, CO2R12, aryl or heteroaryl;
wherein each aryl or heteroaryl is optionally substituted with C1-3alkyl, C1-3alkoxy, halogen, (CH2)nNR10R11 or O(CH2)2-4NR10R11;
or R9 is aryl or heteroaryl optionally substituted with one to three groups selected from C1-3alkyl optionally substituted with phenyl, C1-3alkoxy, halogen, (CH2)nNR10R11, (CH2)nCO2R12; (CH2)nCONR10R11 and O(CH2)2-4NR10R11;
or R8 and R9 together form a saturated or unsaturated 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by OH;
R10 and R11 may be the same or different and are each independently selected from H, OH, C1-3alkoxy, C1-6alkyl branched or unbranched, C3-8cycloalkyl, benzyl and phenyl;
wherein said alkyl, cycloalkyl, benzyl or phenyl are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R12, NR13R14, O(CH2)2-4NR13R14 or phenyl;
or R10 and R11 together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C1-3 alkyl, C1-3alkoxy, OH or xe2x80x94(CH2)nNR13R14;
R12 is H or C1-6alkyl optionally substituted with phenyl, OH, C1-3alkoxy or NR13R14;
R13 and R14 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3alkoxy, OH or phenyl;
or R13 and R14 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2; and
R15 is H.
In another embodiment of the invention, there are provided compounds of the formula (I) as described immediately above, and wherein:
Ar1 is phenyl, or pyridyl;
X is NH or Nxe2x80x94CH3;
Y is NH and
Ra is H, hydroxyC1-2alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo-propyl, vinyl or C3-5alkynyl substituted by C1-3alkoxy or phenyl;
R1 and R2 are the same or different and selected from: halogen, C1-3 alkyl, wherein the C1-3 alkyl are optionally partially or fully halogenated, NO2, NR13R14;
R3 is H, halogen, methoxy or methyl;
R4 and R5 together complete a fused ring of formula B; R8 is H, C1-3alkyl optionally substituted with OH; or R8 is (CH2)2-3NR10R11 or CO2R12;
R9 is methyl or C2-3 alkenyl each being optionally substituted with one or more OH, CN, NR10R11, CONR10R11 or CO2R12;
or R9 is heteroaryl optionally substituted with one to three groups selected from C1-3alkyl optionally substituted with phenyl, C1-3alkoxy, halogen or amino;
R10 and R11 may be the same or different and are each independently selected from H, OH, C1-3alkoxy, C1-3alkyl branched or unbranched, optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R12, NR13R14, O(CH2)2-4NR13R14 or phenyl;
or R10 and R11 together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C1-3 alkyl, C1-3alkoxy or OH;
R12 is H or C1-3alkyl optionally substituted with phenyl, OH, C1-3alkoxy or NR13R14;
R13 and R14 are each independently selected from H and C1-3alkyl optionally substituted with C1-3alkoxy or OH;
or R13 and R14 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2.
In yet another embodiment of the invention there are provided compounds of the formula (I) as described immediately above, and wherein:
Ar1 is phenyl;
Ra is H or hydroxymethyl;
R1 and R2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO2 and NH2;
R3 is H, chloro, fluoro, bromo or methoxy;
R10 and R11 may be the same or different and are each independently selected from H, OH, methoxy, C1-3alkyl branched or unbranched, optionally substituted with OH, NR13R14 or phenyl;
or R10and R11 together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C1-2 alkyl; and
R12 is C1-3alkyl optionally substituted with morpholino.
In still another embodiment of the invention there are provided compounds of the formula (Ia): 
wherein:
X is NH, Nxe2x80x94C1-3alkyl, N-cyclopropyl, S or O;
Ra is H, C1-10alkyl, C2-10alkenyl or C2-10alkynyl, each of which may be branched or cyclic; or Ra is aryl or heteroaryl;
wherein each Ra is independently optionally substituted with one or more C1-6alkyl, C1-6 alkoxy, halogen, OH, oxo, NR10R11, aryl or heteroaryl each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, C1-3alkyl, C1-3alkoxy, hydroxyC1-3alkyl and (CH2)mNR10R11; and wherein Ra is attached at the 4- or 5-position;
R1 and R2 are the same or different and selected from H, halogen, CN, NO2, C1-10 branched or unbranched saturated or unsaturated alkyl, C1-10 branched or unbranched alkoxy, C1-10 branched or unbranched acyl, C1-10 branched or unbranched acyloxy, C1-10 branched or unbranched alkylthio, aminosulfonyl, di-(C1-3)alkylaminosulfonyl, NR10R11, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the abovementioned R1 and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NR10R11, C1-6 branched or unbranched alkyl, C3-7cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(C1-3)alkylaminocarbonyl;
R3 is H, halogen, OH, (CH2),NR10R11, CONR10R11, (CH2)nCO2R12; C1-3alkyl optionally substituted with OH, C1-3 alkoxy optionally halogenated or C1-3 alkylthio;
R4 and R5 together with the atoms to which they are attached complete a fused ring system of the formulas A or B: 
R6 is C1-3alkyl or H;
R7 is C1-6alkyl branched or unbranched or H;
R8 is H, C1-6alkyl branched or unbranched, saturated or unsaturated, optionally substituted with phenyl, OH or C1-3alkoxy; or R8 is (CH2)mNR10R11, (CH2)mNR10COR12, (CH2)nCO2R12, (CH2)nCONR10R11 or R8 is phenyl or heteroaryl, each being optionally substituted with C1-3alkyl, C1-3alkoxy, OH, xe2x80x94SO3H or halogen;
R9 is H, CN or CONR10R11; or R9 is C1-10alkyl branched or unbranched, C3-10cycloalkyl, C5-7cycloalkenyl, C2-6 alkenyl, C2-6 alkynyl each being optionally substituted with one or more C3-10cycloalkyl, C3-10cycloalkylidene, C5-7cycloalkenyl, halogen, OH, oxo, CN, C1-3-alkoxy, C1-3acyloxy, NR10R11, NR10CONR10R11, NR10C(xe2x95x90NR10)NR10R11, NR10COR12, NR10S(O)pR12, SR12, CONR10R11, CO2R12, C(R10)xe2x95x90NNR10R11, C(R10)xe2x95x90NNR10CONR10R11, aryloxy, arylthio, aryl or heteroaryl; wherein each aryloxy, arylthio, aryl or heteroaryl is optionally substituted with C1-3alkyl, C1-3alkoxy, halogen, (CH2)nNR10R11 or O(CH2)2-4NR10R11;
or R9 is aryl, heteroaryl, or heterocycle, wherein each aryl, heteroaryl or heterocycle is optionally substituted with one to three groups selected from C1-3alkyl optionally substituted with phenyl or NR10C(xe2x95x90NR10)NR10R11, C1-3alkoxy, halogen, CN, oxo, (CH2)nNR10R11, (CH2)nCO2R12; (CH2)nCONR10R11 and O(CH2)2-4NR10R11;
or R8 and R9 together form a saturated or unsaturated 5 or 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by one or two C1-3alkyl, OH, oxo or (CH2)nNR10R11, or optionally spiro-fused to a 1,3 dioxolane group or 1,3 dithiolane group, each 1,3 dioxolane group or 1,3 dithiolane group optionally substituted by C1-6alkyl, C1-6alkoxy, OH or (CH2)nNR10R11;
R10 and R11 may be the same or different and are each independently selected from H, OH, C1-3alkoxy, C1-6alkyl branched or unbranched, C3-8cycloalkyl, aryl, arylC1-3alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylC1-3alkyl or heteroaryl are optionally substituted with OH, C1-3alkoxy, CN, NO2, C1-3acyloxy, CO2R12, NR13R14, O(CH2)2-4NR13R14, aryl or heteroaryl;
or R10 and R11 together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached; wherein said alkylene chain is optionally interrupted by O, S(O)p, and NR13; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3 alkoxy, OH, xe2x80x94(CH2)nNR13R14, CONR13R14 or NR13COR14;
R12 is H, C1-6alkyl or C3-8cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C1-3alkoxy or NR13R14; or R12 is phenyl or heterocycle, optionally substituted with one to three groups selected from C1-3alkyl, C1-3alkoxy, halogen, (CH2)mNR10R11, (CH2)nCONR10R11 and O(CH2)2-4NR10R11;
R13 and R14 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3 alkoxy, OH or phenyl;
or R13 and R14 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2;
m is 1-4, n is 0-3 and p is 0-2; and
the pharmaceutically acceptable acid or salt derivatives thereof.
In another embodiment of the invention, there are provided compounds of the formula (Ia) as described above, wherein:
X is NH or Nxe2x80x94CH3;
Ra is H, hydroxyC1-2 alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo-propyl, vinyl or C3-5alkynyl substituted by C1-3alkoxy or phenyl; and wherein Ra is attached at the 4-position;
R1 and R2 are the same or different and selected from: H, halogen, C1-3 alkyl, wherein the C1-3 alkyl is optionally partially or fully halogenated, NO2, NR13R14;
R3 is H, halogen, methoxy or methyl;
R4 and R5 together complete a fused ring of formula B;
R8 is H, C1-3alkyl optionally substituted with OH; or R8 is (CH2)2-3NR10R11 or CO2R12;
R9 is CN; or R9 is methyl, C2-3 alkenyl or C2-3 alkynyl, each being optionally substituted with one or more C5-7 cycloalkylidene, C5-7cycloalkenyl, OH, CN, NR10R11, NR10CONR10R11,NR10COR12, NR10S(O)pR12, CONR10R11, CO2R12, C(R10)xe2x95x90NNR10R11 or heteroaryl;
or R9 is aryl or heteroaryl optionally substituted with one to three groups selected from C1-3alkyl optionally substituted with phenyl, C1-3alkoxy, halogen, amino or CONH2;
or R8 and R9 together form a cyclopentene ring spiro-fused to a 1,3 dioxolane group, said 1,3 dioxolane group being optionally substituted by C1-3alkyl, C1-3alkoxy, OH or (CH2)pNR10R11;
R10 and R11 may be the same or different and are each independently selected from H, OH, C1-3alkoxy, C1-3alkyl branched or unbranched, C5-7cycloalkyl or phenyl, wherein said alkyl, cycloalkyl or phenyl are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, NO2, CO2R12, NR13R14, O(CH2)24NR13R14 or phenyl;
or R10 and R11 together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C1-3 alkyl, C1-3alkoxy,OH, (CH2)nNR13R14, CONR13R14 or NR13COR14;
R12 is H, C1-3alkyl or C5-7cycloalkyl, each optionally substituted with phenyl, OH, C1-3alkoxy or NR13R14; or R12 is phenyl or is a saturated, 4- to 6-membered nitrogen-containing heterocycle, each optionally substituted with one to three groups selected from C1-3alkyl, C1-3alkoxy, halogen, (CH2)mNR10R11, (CH2)nCONR10R11 and O(CH2)2-4NR10R11;
R13 and R14 are each independently selected from H and C1-3alkyl optionally substituted with C1-3alkoxy or OH;
or R13 and R14 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2.
In yet another embodiment of the present invention, there are provided compounds of the formula (Ia) described immediately above, wherein:
Ra is H or hydroxymethyl;
R1 and R2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO2 and NH2;
R3 is H, chloro, fluoro, bromo or methoxy;
R10 and R11 may be the same or different and are each independently selected from H, OH, methoxy, C1-3alkyl branched or unbranched or C5-7cycloalkyl, wherein said alkyl or cycloalkyl are optionally substituted with OH, NR13R14 or phenyl;
or R10 and R11 together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C1-2 alkyl, NR13R14, CONR13R14 or NR13COR14; and
R12 is C1-3alkyl optionally substituted with morpholino; or R12 is phenyl or is azetidinyl, pyrrolidinyl or piperidinyl, each optionally substituted with one to three groups selected from C1-3alkyl, C1-3alkoxy and halogen.
In still another subgeneric embodiment of the invention there are provided compounds of the formula (Ia): 
wherein:
X is NH, Nxe2x80x94C1-3alkyl, N-cyclopropyl, S or O,
Ra is H, C1-10alkyl, C2-10alkenyl or C2-10alkynyl, each of which may be branched or cyclic;
or Ra is aryl or heteroaryl;
wherein each Ra is independently optionally substituted with one or more C1-6 alkoxy, halogen, OH, oxo, NR10R11, aryl or heteroaryl each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, C1-3alkyl, C1-3alkoxy, hydroxyC1-3alkyl and (CH2)mNR10R11; and wherein Ra is attached at the 4- or 5-position;
R1 and R2 are the same or different and selected from H, halogen, CN, NO2, C1-10 branched or unbranched saturated or unsaturated alkyl, C1-10 branched or unbranched alkoxy, C1-10 branched or unbranched acyl, C1-10 branched or unbranched acyloxy, C1-10 branched or unbranched alkylthio, aminosulfonyl, di-(C1-3)alkylaminosulfonyl, NR10R11, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the above mentioned R1 and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NR10R11, C1-6 branched or unbranched alkyl, C3-7cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(C1-3)alkylaminocarbonyl;
R3 is H, halogen, OH, (CH2)nNR10R11, (CH2)nCO2R12; C1-3alkyl optionally substituted with OH, C1-3 alkoxy optionally halogenated or C1-3 alkylthio;
R4 and R5 together with the atoms to which they are attached complete a fused ring system of the formulas A or B: 
R6 is C1-3alkyl or H;
R7 is C1-6alkyl branched or unbranched or H;
R8 is H, C1-6alkyl branched or unbranched, saturated or unsaturated, optionally substituted with phenyl, OH or C1-3alkoxy; or R8 is (CH2)mNR10R11, (CH2)mNR10COR12, (CH2)nCO2R12, (CH2)nCONR10R11 or R8 is phenyl or heteroaryl, each being optionally substituted with C1-3alkyl, C1-3alkoxy, OH, xe2x80x94SO3H or halogen;
R9 is H; or R9 is C1-10alkyl branched or unbranched, C3-10cycloalkyl, C2-6 alkenyl, C2-6alkynyl each being optionally substituted with one or more halogen, OH, oxo, CN, C1-3alkoxy, NR10R11, NR10COR12, SR12, CONR10R11CO2R12, aryloxy, arylthio, aryl or heteroaryl; wherein each aryloxy, arylthio, aryl or heteroaryl is optionally substituted with C1-3alkyl, C1-3alkoxy, halogen, (CH2)nNR10R11 or O(CH2)2-4NR10R11;
or R9 is aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one to three groups selected from C1-3alkyl optionally substituted with phenyl, C1-3alkoxy, halogen, (CH2)nNR10R11, (CH2)nCO2R12; (CH2)nCONR10R11 and O(CH2)2-4NR10R11;
or R8 and R9 together form a saturated or unsaturated 6 membered aromatic or nonaromatic carbocyclic ring optionally substituted by one or two OH, oxo or (CH2)nNR10R11;
R10 and R11 may be the same or different and are each independently selected from H, OH, C1-3alkoxy, C1-6alkyl branched or unbranched, C3-8cycloalkyl, aryl, arylC1-3alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylC1-3alkyl or heteroaryl are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R12, NR13R14, O(CH2)2-4NR13R14, aryl or heteroaryl;
or R10 and R11 together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached; wherein said alkylene chain is optionally interrupted by O, S(O)p and NR13; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, OH or xe2x80x94(CH2)nNR13R14;
R12 is H, C1-6alkyl or C3-8cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C1-3alkoxy or NR13R14; or R12 is phenyl, optionally substituted with one to three groups selected from C1-3alkyl, C1-3alkoxy, halogen, (CH2)mNR10R11, (CH2)nCONR10R11 and O(CH2)2-4NR10R11;
R13 and R14 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3alkoxy, OH or phenyl;
or R13 and R14 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2;
m is 1-4, n is 0-3 and p is 0-2; and
the pharmaceutically acceptable acid or salt derivatives thereof.
In another embodiment of the invention there are provided compounds of the formula (Ia) as described immediately above, and wherein:
X is NH or Nxe2x80x94CH3;
Ra is H, hydroxyC1-2 alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo-propyl, vinyl or C3-5alkynyl substituted by C1-3alkoxy or phenyl; and wherein Ra is attached at the 4-position;
R1 and R2 are the same or different and selected from: halogen, C1-3 alkyl, wherein the C1-3 alkyl is optionally partially or fully halogenated, NO2, NR13R14;
R3 is H, halogen, methoxy or methyl;
R4 and R5 together complete a fused ring of formula B;
R8 is H, C1-3alkyl optionally substituted with OH; or R8 is (CH2)2-3NR10R11 or CO2R12;
R9 is methyl or C2-4 alkenyl each being optionally substituted with one or more OH, CN, NR10R11, CONR10R11 or CO2R12;
or R9 is heteroaryl optionally substituted with one to three groups selected from C1-3alkyl optionally substituted with phenyl, C1-3alkoxy, halogen or (CH2)nNR10R11;
R10 and R11 may be the same or different and are each independently selected from H, OH, C1-3alkoxy, C1-3alkyl branched or unbranched, optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R12, NR13R14, O(CH2)2-4NR13R14 or phenyl;
or R10 and R11 together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C1-3 alkyl, C1-3alkoxy or OH;
R12 is H or C1-3alkyl optionally substituted with phenyl, OH, C1-3alkoxy or NR13R14;
R13 and R14 are each independently selected from H and C1-3alkyl optionally substituted with C1-3alkoxy or OH;
or R13 and R14 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2.
In still a further embodiment of the invention there are provided compounds of the formula (Ia) as described immediately above, and wherein:
Ra is H or hydroxymethyl;
R1 and R2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO2 and NH2;
R3 is H, chloro, fluoro, bromo or methoxy;
R10 and R11 may be the same or different and are each independently selected from H, OH, methoxy, C1-3alkyl branched or unbranched, optionally substituted with OH, NR13R14 or phenyl;
or R10 and R11 together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C1-2 alkyl; and
R12 is C1-3alkyl optionally substituted with morpholino.
In another aspect of the invention, there are provided intermediate compounds of the formula(III) useful in the synthetic schemes and examples set forth below. In yet another aspect of the invention are particular intermediate compounds of the formula(III), (representative examples shown Table 1 below) which possess physiological activity.
In their broadest generic aspect, intermediate compounds described above are represented by the formula (III): 
wherein:
Ar1 is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle; wherein said carbocycle, heteroaryl or heterocycle is optionally substituted by one or more R1, R2 and R3;
X is NH, Nxe2x80x94C1-3alkyl, N,cyclopropyl, S or O,
Y is NR15, S or O;
Ra is H, C1-10alkyl, C2-10 alkenyl or C2-10 alkynyl, each of which may be branched or cyclic; or Ra is aryl or heteroaryl;
wherein each Ra is independently optionally substituted with one or more C1-3alkyl, C1-6 alkoxy, halogen, OH, oxo, NR10 R11, aryl or heteroaryl each aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, OH, C1-3alkyl, C1-3alkoxy, hydroxyC1-3alkyl and (CH2)mNR10R11; and wherein Ra is attached at the 4- or 5-position;
R1 and R2 are the same or different and selected from H, halogen, CN, NO2, C1-10 branched or unbranched saturated or unsaturated alkyl, C1-10 branched or unbranched alkoxy, C1-10 branched or unbranched acyl, C1-10 branched or unbranched acyloxy, C1-10 branched or unbranched alkylthio, aminosulfonyl, di-(C1-3)alkylaminosulfonyl, NR10R11, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein the abovementioned R1 and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from oxo, OH, NR10R11, C1-6 branched or unbranched alkyl, C3-7cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(C1-3)alkylaminocarbonyl;
R3 is H, halogen, OH, (CH2)nNR10R11, (CH2)nCO2R12; C1-3alkyl optionally substituted with OH, C1-3 alkoxy optionally halogenated or C1-3 alkylthio;
R4 and R5 together with the atoms to which they are attached complete a fused ring system of the formula C: 
R6 is C1-3alkyl or H;
R7 is C1-6alkyl branched or unbranched or H;
R10 and R11 may be the same or different and are each independently selected from H, OH, C1-3alkoxy, C1-6alkyl branched or unbranched, C3-8cycloalkyl, aryl, arylC1-3alkyl and heteroaryl; wherein said alkyl, cycloalkyl, aryl, arylC1-3alkyl or heteroaryl are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R12, NR13R14, O(CH2)2-4NR13R14, aryl or heteroaryl;
or R10 and R11 together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached; wherein said alkylene chain is optionally interrupted by O, S(O)p and NR13; and wherein said ring is optionally substituted by C1-3 alkyl, C1-3alkoxy, OH or xe2x80x94(CH2)nNR13R14;
R12 is H, C1-6alkyl or C3-8cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C1-3alkoxy or NR13R14; or R12 is phenyl, optionally substituted with one to three groups selected from C1-3alkyl, C1-3alkoxy, halogen, (CH2)mNR10R11, (CH2)nCONR10R11 and O(CH2)2-4NR10R 11;
R13 and R14 are each independently selected from H and C1-6 alkyl optionally substituted with alkoxy, OH or phenyl;
or R13 and R14 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2; and
m is 1-4, n is 0-3 and p is 0-2.
One embodiment of the compounds of formula(III) are those wherein:
Ar1 is
a) a cycloalkyl group selected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl;
b) a cycloalkenyl group selected from cyclopentenyl, cyclohexenyl, cycloheptenyl;
c) phenyl, naphthyl; indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl;
d) heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl, and indazolyl, or a fused heteroaryl selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; or
e) a heterocycle selected from: pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl;
wherein each of the above Arl are optionally substituted by one or more R1, R2 and R3 as hereinabove defined;
Ra is H, C1-6alkyl, C2-5alkenyl, C2-5alkynyl, phenyl or heteroaryl selected from: pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, furyl, thiazolyl and thienyl; each Ra being optionally substituted with one or more phenyl, halogen, C1-3alkyl, C1-3 alkoxy, OH, oxo, or NR10 R11; wherein Ra is at the 4-position;
R3 is H, halogen, methyl, methoxy, hydroxymethyl or OH;
R6 is C1-3alkyl or H;
R7 is C1-6alkyl branched or unbranched or H;
R10 and R11 may be the same or different and are each independently selected from H, OH, C1-3alkoxy, C1-6alkyl branched or unbranched, C3-8cycloalkyl, benzyl and phenyl;
wherein said alkyl, cycloalkyl or phenyl are optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R12, NR13R14, O(CH2)2-4NR13R14 or phenyl;
or R10 and R11 together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C1-3 alkyl, C1-3alkoxy, OH or xe2x80x94(CH2)nNR13R14;
R12 is H or C1-6alkyl optionally substituted with phenyl, OH, C1-3alkoxy or NR13R14;
R13 and R14 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3alkoxy, OH or phenyl; and
or R13 and R14 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2.
Another embodiment of the compounds of the formula(III) are those described immediately above, and wherein:
Ar1 is phenyl, or pyridyl;
X is NH or Nxe2x80x94CH3;
Y is NH and
Ra is H, hydroxyC1-2alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl, 3-hydroxy-2-oxo-propyl, vinyl or C3-5alkynyl substituted by C1-3alkoxy or phenyl;
R1 and R2 are the same or different and selected from: halogen, C1-3 alkyl, wherein the C1-3 alkyl are optionally partially or fully halogenated, NO2, NR13R14;
R3 is H, halogen, methoxy or methyl;
R10 and R11 may be the same or different and are each independently selected from H, OH, C1-3alkoxy, C1-3alkyl branched or unbranched, optionally substituted with OH, C1-3alkoxy, C1-3acyloxy, CO2R12, NR13R14, O(CH2)2-4NR13R14 or phenyl;
or R10 and R11 together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C1-3 alkyl, C1-3alkoxy or OH;
R12 is H or C1-3alkyl optionally substituted with phenyl, OH, C1-3alkoxy or NR1-3R14;
R13 and R14 are each independently selected from H and C1-3alkyl optionally substituted with C1-3alkoxy or OH;
or R13 and R14 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2.
In yet another embodiment of the compounds of formula(III) are those described immediately above, and wherein:
Ar1 is phenyl;
Ra is H or hydroxymethyl;
R1 and R2 are the same or different and selected from: halogen, methyl optionally partially or fully halogenated, NO2 and NH2;
R3 is H, chloro, fluoro, bromo or methoxy;
R10and R11 may be the same or different and are each independently selected from H, OH, methoxy, C1-3alkyl branched or unbranched, optionally substituted with OH, NR13R14 or phenyl;
or R10 and R11 together form morpholino, pyrrolidinyl, piperazinyl or piperidinyl each optionally substituted by C1-2 alkyl; and
R12 is C1-3alkyl optionally substituted with morpholino.
In a further embodiment of the invention, there are provided the following compounds of the formulas (I) and (Ia):
2-(2,6-Dichlorophenylamino)-6,7-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-3,5-dihydro-imidazo[4,5-i]phenanthridin-4-one;
2-(2,6-Dichlorophenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-7-methyl-1,8-dihydro-imidazo [4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinolin-6-acetic acid ethyl ester;
3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylic acid methyl ester;
2-(2,6-Dichlorophenylamino)-1,7-dimethyl-6-(2-hydroxyethyl)-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinoline-6-carboxylic acid methyl ester;
2-(2,6-Dichlorophenylamino)-1,7-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9one;
3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylic acid methyl ester;
3-[2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinolin-6-yl]propionic acid ethyl ester
N-Benzyl-N-methyl-2-[(2,6-dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinolin-6-yl] acetamide;
2-(2,6-Dichlorophenylamino)-1,7-dimethyl-6-(2-morpholin-4-ylethyl)-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2-Chloro-6-methylphenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(4-Bromo-2-dichlorophenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1 H-imidazo[4,5-h]isoquinolin-7-yl]-N-methoxy-N-methylacrylamide;
2-(2-Chloro-6-nitrophenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
N-Benzyl-3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylamide;
3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylic acid 4-morpholine amide;
2-(2,6-Dichlorophenylamino)-1,7-dimethyl -6-[3-(4-morpholino)propyl]-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-4-hydroxymethyl-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dimethylphenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2-Ethyl-6-methylphenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-1,7-dimethyl-6-(3-phenylaminopropyl)-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino-6-{3-[4-(2-diethylaminoethoxy)-phenylamino]propyl}-1,7-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2-Bromo-6-chloro-4-fluorophenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-4-(2-hydroxyethylaminomethyl)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-4-(4-methoxybenzylaminomethyl)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-vinyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-4-(2,6-difluoropyridin-3yl)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-4-(3-methylphenyl)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinoline-6-carboxylic acid 2-(4-moropholino)ethyl ester;
2-(2,6-Dichlorophenylamino)-4-(3-hydroxy-2-oxo-propyl)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
N-4-(2-Diethylaminoethoxy)phenyl-3-[2-(2,6-dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylamide;
3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-N-methyl acrylamide;
9-Hydroxy-2-(2,6-dichlorophenylamino)-3,5,6,7,8,9-hexahydro-imidazo[4,5-i]phenanthridin-4-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-hydroxypropen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(2-phenylethenyl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2-Amino-6-chlorophenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-1,6,7-trimethyl-4-vinyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-4-(3-methoxypropyn1-yl)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-1,6,7trimethyl-4-(5-phenylpent-1-ynyl)-I1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-oxazol-5-yl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-vinyl-1,8-dihydro-imidazo[4,5-h]isoquinoline 9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-morpholin-4-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,7-dimethyl-6-[2-(2-hydroxyethyl)aminoethyl]-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
3-[2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylonitrile;
2-(2-Chloro-6-methylphenylamino)-1,7-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-oxazol-5-yl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,7-dimethyl-6-(3-hydroxypropyl)-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-7-(3-hydroxypropen-1-yl)-1-methyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2-Chloro-6-methylphenylamino)-7-(3-hydroxypropen-1-yl)-1-methyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-(3-diethylaminopropen-1-yl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
7-(3-Aminopropen-1-yl)-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-pyrrolidin-1-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
7-(3-Benzylmethylaminopropen-1-yl)2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichloro-4-methoxyphenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichloro-4-methoxyphenylamino)-1,6-dimethyl-7-oxazol-5-yl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-(3-diethylaminopropen-1-yl)-1-methyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dimethylphenylamino)-1,7-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(4-methylpiperazin-1-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-piperidin-1-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-{3-[ethyl(2-hydroxyethyl)amino]propen-1-yl}-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-[3-(3-hydroxypyrrolidin-1-yl)-propen-1-yl]-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
7-(3-Dibutylaminopropen-1-yl)-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-{3-[(2-methoxyethyl)methylamino]propen-1-yl}-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
7-(3-Diethylaminopropen-1-yl)-1,6-dimethyl-2-(2,6-dimethylphenylamino)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-{3-[(2-diethylaminoethyl)methylamino]-propen-1-yl}-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
7-(3-Diethylaminopropen-1-yl)-1,6-dimethyl-2-(2,4,6-trichlorophenylamino)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
2-(2,6-Dichlorophenylamino)-6-methyl-7-oxazol-5-yl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-[3-(2-pyrrolidin-1-ylmethylpyrrolidin-1-yl)-propen-1-yl]-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
7-[3-(2S-Aminomethylpyrrolidin-1-yl)-propen-1-yl]-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
1-{3-[2-(2,6-Ddichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-L-proline carboxamide
1-{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-piperidine-3-carboxamide
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(methylhydrazonomethyl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
7-[3-(3-Aminopyrrolidin-1-yl)-propen-1-yl]-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-[3-(3-acetamidopyrrolidin-1-yl)-propen-1-yl]-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-[3-(3-dimethylaminopyrrolidin-1-yl)-propen-1-yl]-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
1-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-piperidine-2-carboxamide
7-[3-(3-Aminomethylpiperidin-1-yl)-propen-1-yl]-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
1-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-piperidine-3-carboxylic acid diethylamide
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-ethynyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
1-{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-3-methyl urea
Cyclohexane carboxylic acid {3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide
2-(2,6-Dichlorophenylamino)-1-methyl-7-phenyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one
N-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}methanesulfonamide
3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl urea
1-Cyclohexyl-3-{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H -imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-urea
N-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}benzenesulfonamide
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-ethylaminopropen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
N-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-guanidine
Piperidine-3-carboxylic acid {3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide
L-Proline {3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide
D-Proline {3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide
3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-benzamide
L-Azetidine-2-carboxylic acid {3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide
Piperidine-2-carboxylic acid {3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide;
2-(2-Chloro-6-methylphenylamino)-7-(3-diethylaminopropen-1-yl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-{3-[(3-dimethylamino-propyl)methylamino]-propen-1-yl}-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-[3-(2-diethylaminoethylthio)-propen-1-yl]-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-dimethylaminopropen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
7-(3-N-Cyclohexyl-N-methylaminopropen-1-yl)-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-N-isopropyl-N-methylaminopropen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one; and
the pharmaceutically acceptable derivatives thereof.
In yet still a further embodiment of the invention, there are provided the following compounds of the formulas (I) and (Ia):
2-(2,6-Dichlorophenylamino)-3,5-dihydro-imidazo[4,5-i]phenanthridin-4-one;
2-(2,6-Dichlorophenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-1,7-dimethyl-6-(2-hydroxyethyl)-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinoline-6-carboxylic acid methyl ester;
3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylic acid methyl ester;
2-(2-Chloro-6-methylphenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-N-methoxy-N-methylacrylamide;
2-(2-Chloro-6-nitrophenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
N-Benzyl-3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylamide;
3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylic acid 4-morpholine amide;
2-(2,6-Dichlorophenylamino)-4-hydroxymethyl-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-vinyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinoline-6-carboxylic acid 2-(4-moropholino)ethyl ester;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-hydroxypropen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-oxazol-5-yl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-vinyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-morpholin-4-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
3-[2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylonitrile;
2-(2-Chloro-6-methylphenylamino)-1,7-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;
2-(2,6-Dichlorophenylamino)-1-methyl-7-oxazol-5-yl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-(3-hydroxypropen-1-yl)-1-methyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2-Chloro-6-methylphenylamino)-7-(3-hydroxypropen-1-yl)-1-methyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-(3-diethylaminopropen-1-yl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-pyrrolidin-1-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-(3-diethylaminopropen-1-yl)-1-methyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(4-methylpiperazin-1-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-piperidin-1-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-{3-[ethyl(2-hydroxyethyl)amino]propen-1-yl}-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
7-(3-Diethylaminopropen-1-yl)-1,6-dimethyl-2-(2,6-dimethylphenylamino)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-{3-[(2-diethylaminoethyl)methylamino]-propen-1-yl}-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
7-(3-Diethylaminopropen-1-yl)-1,6-dimethyl-2-(2,4,6-trichlorophenylamino)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
2-(2,6-Dichlorophenylamino)-6-methyl-7-oxazol-5-yl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-[3-(2-pyrrolidin-1-ylmethylpyrrolidin-1 -yl)-propen-1-yl]-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
7-[3-(2S-Aminomethylpyrrolidin-1-yl)-propen-1-yl]-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
1-{3-[2-(2,6-Ddichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-L-proline carboxamide
1-{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-piperidine-3-carboxamide
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(methylhydrazonomethyl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
7-[3-(3-Aminopyrrolidin-1-yl)-propen-1-yl]-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-[3-(3-acetamidopyrrolidin-1-yl)-propen-1-yl]-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-[3-(3-dimethylaminopyrrolidin-1-yl)-propen-1-yl]-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
1-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-piperidine-2-carboxamide
7-[3-(3-Aminomethylpiperidin-1-yl)-propen-1-yl]-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
1-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-piperidine-3-carboxylic acid diethylamide
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-ethynyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
1-{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-3-methyl urea
Cyclohexane carboxylic acid {3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl} amide
2-(2,6-Dichlorophenylamino)-1-methyl-7-phenyl-1,8-dihydro-imidazo[4,5-h] isoquinolin-9-one
N-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl } methanesulfonamide
3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl urea
25 1-Cyclohexyl-3-{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl }-urea
N-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl} benzenesulfonamide
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-ethylaminopropen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one
N-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-guanidine
Piperidine-3-carboxylic acid {3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl} amide
L-Proline {3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl} amide
D-Proline {3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1 H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl} amide
3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1 H-imidazo[4,5-h]isoquinolin-7-yl]-benzamide
L-Azetidine-2-carboxylic acid {3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide
Piperidine-2-carboxylic acid {3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl} amide;
2-(2-Chloro-6-methylphenylamino)-7-(3-diethylaminopropen-1-yl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-{3-[(3-dimethylamino-propyl)methylamino]-propen-1-yl}-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-7-[3-(2-diethylaminoethylthio)-propen-1-yl]-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-dimethylaminopropen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
7-(3-N-Cyclohexyl-N-methylaminopropen-1-yl)-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;
2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-N-isopropyl-N-methylaminopropen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one; and
the pharmaceutically acceptable derivatives thereof.
Any compounds of this invention containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be in the R or S configuration, or a combination of configurations.
Some of the compounds of the invention can exist in more than one tautomeric form. The invention includes all such tautomers.
The compounds of the invention are only those which are contemplated to be xe2x80x98chemically stablexe2x80x99 as will be appreciated by those skilled in the art. For example, a compound which would have a xe2x80x98dangling valencyxe2x80x99, or a xe2x80x98carbanionxe2x80x99 are not compounds contemplated by the invention.
All terms as used herein in this specification, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. For example, xe2x80x9cC1-6alkoxyxe2x80x9d is a C1-6alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, pentoxy and hexoxy. All alkyl, alkylene or alkynyl groups shall be understood as being branched or unbranched unless otherwise specified. Other more specific definitions are as follows:
The term xe2x80x9chalogenxe2x80x9d as used in the present specification shall be understood to mean bromine, chlorine, fluorine or iodine.
The term xe2x80x9cheteroarylxe2x80x9d refers to a stable 5-8 membered (but preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic aromatic heterocycle radical. Each heterocycle consists of carbon atoms and from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur. The heterocycle may be attached by any atom of the cycle, which results in the creation of a stable structure. Example xe2x80x9cheteroarylxe2x80x9d radicals include, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl, 2,4-dioxo-quinazolinyl, imidazo[4,5-c]pyridinyl and indazolyl, or a fused heteroaryl such as cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene;
The term xe2x80x9cheterocyclexe2x80x9d refers to a stable 4-8 membered (but preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic heterocycle radical which may be either saturated or unsaturated, and is non-aromatic. Each heterocycle consists of carbon atoms and from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur. The heterocycle may be attached by any atom of the cycle, which results in the creation of a stable structure. Example xe2x80x9cheterocyclexe2x80x9d radicals include azetidinyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl,indolinyl, 2,3-dihydrobenzimidazolyl and 2,3-dihydro-1-H-imidazo[4,5-c] pyridinyl. As used herein and throughout this specification, the terms xe2x80x9cnitrogenxe2x80x9d and xe2x80x9csulfurxe2x80x9d and their respective elements symbols include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen.
The term xe2x80x9carylxe2x80x9d shall be understood to mean a 6-10 membered aromatic carbocycle, xe2x80x9carylxe2x80x9d includes, for example, phenyl and naphthyl; other terms comprising xe2x80x9carylxe2x80x9d will have the same definition for the aryl component, examples of these moieties include: arylalkyl, aryloxy or arylthio.
The term xe2x80x9ccarbocyclexe2x80x9d shall be understood to mean a 3-10 membered aromatic or nonaromatic cyclic carbon chain. Examples of nonaromatic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl and the like. Examples of aromatic carbocycles include the xe2x80x9carylxe2x80x9d compounds as described hereinabove.
The term xe2x80x9cacylxe2x80x9d shall be understood to mean an Rxe2x80x94(Cxe2x95x90O)xe2x80x94 moiety wherein R is an alkyl. Examples of R can be a C1-10 alkyl, saturated or unsaturated, branched or unbranched, or R can be xe2x80x9carylxe2x80x9d as defined hereinabove. xe2x80x9cAcyloxyxe2x80x9d shall be understood to mean an Rxe2x80x94CO2xe2x80x94 group wherein R is as defined in this paragraph.
The invention includes pharmaceutically acceptable derivatives of compounds of the invention. A xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d refers to any pharmaceutically acceptable salt or ester of a compound of this invention, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound of this invention, a pharmacologically active metabolite or pharmacologically active residue thereof.
Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of this invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and Nxe2x80x94(C1-C4 alkyl)4+ salts.
In addition, the compounds of this invention include prodrugs of compounds of the invention. Prodrugs include those compounds that, upon simple chemical transformation, are modified to produce a compound of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction, enzymatically, metabolically or otherwise. Specifically, when a prodrug of this invention is administered to a patient, the prodrug may be transformed into a compound of the invention, thereby imparting the desired pharmacological effect.
The compounds of the invention may be prepared by the methods described below. Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Typically, reaction progress may be monitered by thin layer chromatography (TLC) if desired. If desired, intermediates and products may be purified by chromatography on silica gel and/or recrystallization. Starting materials and reagents are either commercially available or may be prepared by one skilled in the art using methods described in the chemical literature.
A general procedure (Method A) that may be used to synthesize compounds of formula (I) is illustrated in Scheme I.

An optionally substituted diamine II is reacted with an aryl isothiocyanate in a suitable solvent such as EtOAc, DMF or THF at about ambient to reflux temperature for about 3 to 24 hr to provide thiourea III. Alternately, one can begin with a salt of II and react with an aryl isothiocyanate in pyridine or in a neutral solvent such as THF in the presence of a suitable base such as triethylamine. Reaction of the thiourea with a suitable activating agent such as 1,3-dicyclohexylcarbodiimide (DCC) or mercuric oxide in a suitable solvent such as THF or DMF at about ambient to reflux temperature provides I or a precursor to I which may undergo further chemical transformation to obtain the desired compound. If desired, one may perform the two steps without isolating the thiourea, by adding DCC or mercuric oxide to the reaction of II and the aryl isothiocyanate.
One may also prepare benzothiazoles (formula I, X=S) by Method A, starting with the analogous aminothiophenol. Preferably, one may also use Method B illustrated in Scheme II and described below.

In this method, an appropriately substituted aniline is reacted with an aryl isothiocyanate as in Method A to provide thiourea V. Reaction of V under cyclizing conditions, such as in the presence of bromine in a suitable solvent such as chloroform at about reflux temperature, provides I (X=S) or a precursor to I.
The starting diamine (II) in Method A may be prepared by reduction of a nitroaniline, for example under hydrogen atmosphere in the presence of a suitable catalyst such as palladium on carbon in a suitable solvent, such as EtOAc or HOAc.
One procedure (Method C) for preparing starting nitroanilines is illustrated in Scheme III and described below.

In Method C, 2,6-dichloro-3-nitrobenzonitrile (VI) is reacted with an amine in a suitable solvent, such as EtOH, THF or EtOAc, optionally in a pressure flask and at about 0 to 80xc2x0C., to provide VII. Reaction of VII with keto-ester VIII in the presence of a suitable base, such as K2CO3, potassium t-butoxide or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in a suitable solvent, such as DMF or DMSO at about ambient temperature provides IX. Hydrolysis and cyclization of IX to provide X is accomplished by reaction with aqueous acid, for example a mixture of acetic acid, sulfuric acid and water at about reflux temperature. Reduction of nitroaniline X, in a suitable solvent, preferably acetic acid and/or trifluoroacetic acid, as described above, provides XI.
In a variation of Method C, one may reduce intermediate IX as described above, to the corresponding diamine and form the benzimidazole by Method A prior to formation of the isoquinolinone.
A procedure for introducing RA into compounds of formula (I) is illustrated in Scheme IV.

Intermediate XII (prepared as described in Scheme III for preparation of IX, followed by reduction) is reacted with bromine in a suitable solvent, such as chloroform at ambient temperature to provide XIII. Intermediate XIII is converted to XIV according to Method A. Cross-coupling chemistry can be used to introduce carbon in place of bromine. For example, reaction with vinyl tributyltin in the presence of a suitable catalyst, such as (PPh3)2PdCl2, in a suitable solvent, such as 1-methyl-2-pyrrolidinone (NMP) at about 100xc2x0 C., provides XV. Alternately, reaction with a terminal alkyne in the presence of a suitable catalyst, such as (PPh3)2PdCl2, and CuI, and a suitable base, such as triethylamine in a solvent such as THF at about ambient temperature provides an alkyne as Ra. Other Ra may be obtained by transformation of these Ra by methods known to those skilled in the art. Several of these transformations are exemplified below.
A method for preparing compounds of the invention in which R4 and R5 represent ring B, which is based on the procedure described in J. Heterocyclic Chem., 1970, 7, 615,is shown in Scheme V.

Intermediate XVI (prepared according to Method A or Method B) is reacted with a reducing agent such as sodium borohydride, in a suitable solvent, such as THF or dioxane, at about 0xc2x0 C. to ambient temperature, to give intermediate XVII, in which one carbonyl of the imide has been reduced selectively. Treatment of XVII with a strong acid, such as sulfuric acid, at ambient temperature, causes rearrangement to the isoquinolone XVIII. It will be appreciated that this method is most suitable for compounds where R6, R7, R8 and R9 are all the same group, preferably methyl. In a variation of this method, the reduction of the imide and rearrangement to the isoquinolone can be carried out prior to forming the benzimidazole ring.
Functional groups at R8 or R9 on compounds of formula (I) or intermediates prepared as illustrated in the Schemes above may also be transformed by methods known to those skilled in the art to prepare additional compounds of the invention. Several of these transformations are also exemplified below.
The compounds of the invention are useful in inhibiting the activity of src-family kinases and PDGFR kinase. In doing so, the compounds are effective in blocking disease processes mediated by these kinases. For example, by inhibiting p56 lck, the compounds block downstream signaling events following T cell activation by antigen. Activation of antigen-specific T cells is necessary for the induction and progression of diseases, including autoimmune diseases, allergic diseases and transplant rejection (J. H. Hanke et al., Inflamm. Res., 1995, 44, 357). Therefore the compounds of the invention are useful for treating such diseases. These include but are not limited to rheumatoid arthritis, multiple sclerosis, Guillain-Barre syndrome, Crohn""s disease, ulcerative colitis, psoriasis, graft versus host disease, systemic lupus erythematosus, insulin-dependent diabetes mellitus and asthma.
In view of their inhibitory effect on src-family kinases and PDGFR kinase, the compounds of the invention are useful in treating cancer. For example, the compounds of the invention are useful in treating src-dependent tumors, such as in mammary carcinoma, colon carcinoma, melanoma and sarcoma, and are also useful in treating PDGF-dependent tumors, such as ovarian cancer, prostate cancer and glioblastoma. In view of their inhibitory effect on src kinase, the compounds of the invention are also useful in treating conditions involving cerebral ischemia, for example, in reducing brain damage following a stroke.
By inhibiting p60src, compounds of the invention may also be useful in treating osteoporosis, Paget""s disease, bone inflammation and joint inflammation. By inhibiting PDGFR kinase, compounds of the invention may also be useful in treating fibrotic diseases, restenosis and atherosclerosis. By inhibiting lyn kinase, the compounds of the invention may also be useful in enhancing or potentiating the effectiveness of radiation therapy.
For therapeutic use, the compounds of the invention may be administered in any conventional dosage form in any conventional manner. Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by infusion, sublingually, transdermally, orally, rectally, topically or by inhalation. The preferred modes of administration are oral and intravenous. Compositions comprising the compounds of the invention for each of the aforementioned routes of administration will be apparent to the skilled artisan. For example, one embodiment of the invention provides for pharmaceutical compositions including a pharmaceutically effective amount of the compounds according to the invention. Such pharmaceutical compositions will include pharmaceutically acceptable carriers and adjuvants as further described below.
The compounds of this invention may be administered alone or in combination with adjuvants that enhance stability of the inhibitors, facilitate administration of pharmnaceutic compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients. Advantageously, such combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies. Compounds of the invention may be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition. Advantageously, the compounds may then be administered together in a single dosage form. In some embodiments, the pharmaceutical compositions comprising such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of a compound of formula (I) (w/w) or a combination thereof. The optimum percentage (w/w) of a compound of formula(I) may vary and is within the purview of those skilled in the art. Alternatively, the compounds may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regime.
As mentioned above, dosage forms of the compounds of this invention include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances. Preferred dosage forms include, tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch. Methods for preparing such dosage forms are known (see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). Dosage levels and requirements are well-recognized in the art and may be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from about 1-1000 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be given. For oral doses, up to 2000 mg/day may be required. As the skilled artisan will appreciate, lower or higher doses may be required depending on particular factors. For instance, specific dosage and treatment regimens will depend on factors such as the patient""s general health profile, the severity and course of the patient""s disorder or disposition thereto, and the judgment of the treating physician.